The pulmonary vasculature in lethal COVID-19 and idiopathic pulmonary fibrosis at single-cell resolution
Authors: Laura P M H de Rooij, Lisa M Becker, Laure-Anne Teuwen, Bram Boeckx, Sander Jansen, Simon Feys, Stijn Verleden, Laurens Liesenborghs, Anna K Stalder, Sasha Libbrecht, Tina Van Buyten, Gino Philips, Abhishek Subramanian, Sébastien J Dumas, Elda Meta, Mila Borri, Liliana Sokol, Amélie Dendooven, Anh-Co K Truong, Jan Gunst, Pierre Van Mol, Jasmin D Haslbauer, Katerina Rohlenova, Thomas Menter, Robbert Boudewijns, Vincent Geldhof, Stefan Vinckier, Jacob Amersfoort, Wim Wuyts, Dirk Van Raemdonck, Werner Jacobs, Laurens J Ceulemans, Birgit Weynand, Bernard Thienpont, Martin Lammens, Mark Kuehnel, Guy Eelen, Mieke Dewerchin, Luc Schoonjans, Danny Jonigk, Jo van Dorpe, Alexandar Tzankov, Els Wauters, Massimiliano Mazzone, Johan Neyts, Joost Wauters, Diether Lambrechts, Peter Carmeliet
Journal: Cardiovascular Research (2022)

Abstract Aims Severe acute respiratory syndrome coronavirus-2 infection causes COVID-19, which in severe cases evokes life-threatening acute respiratory distress syndrome (ARDS). Transcriptome signatures and the functional relevance of non-vascular cell types (e.g. immune and epithelial cells) in COVID-19 are becoming increasingly evident. However, despite its known contribution to vascular inflammation, recruitment/invasion of immune cells, vascular leakage, and perturbed haemostasis in the lungs of severe COVID-19 patients, an in-depth interrogation of the endothelial cell (EC) compartment in lethal COVID-19 is lacking. Moreover, progressive fibrotic lung disease represents one of the complications of COVID-19 pneumonia and ARDS. Analogous features between idiopathic pulmonary fibrosis (IPF) and COVID-19 suggest partial similarities in their pathophysiology, yet, a head-to-head comparison of pulmonary cell transcriptomes between both conditions has not been implemented to date. Methods and results We performed single-nucleus RNA-sequencing on frozen lungs from 7 deceased COVID-19 patients, 6 IPF explant lungs, and 12 controls. The vascular fraction, comprising 38 794 nuclei, could be subclustered into 14 distinct EC subtypes. Non-vascular cell types, comprising 137 746 nuclei, were subclustered and used for EC-interactome analyses. Pulmonary ECs of deceased COVID-19 patients showed an enrichment of genes involved in cellular stress, as well as signatures suggestive of dampened immunomodulation and impaired vessel wall integrity. In addition, increased abundance of a population of systemic capillary and venous ECs was identified in COVID-19 and IPF. COVID-19 systemic ECs closely resembled their IPF counterparts, and a set of 30 genes was found congruently enriched in systemic ECs across studies. Receptor–ligand interaction analysis of ECs with non-vascular cell types in the pulmonary micro-environment revealed numerous previously unknown interactions specifically enriched/depleted in COVID-19 and/or IPF. Conclusions This study uncovered novel insights into the abundance, expression patterns, and interactomes of EC subtypes in COVID-19 and IPF, relevant for future investigations into the progression and treatment of both lethal conditions.